Physical Sciences Inc. (PSI) has successfully completed a Phase I program to develop a multimodal adaptive optics (AO) retinal imager for diagnosis of retinal diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinitis pigmentosa (RP). The development represents the first ever high performance AO system constructed that combines AO- corrected scanning laser ophthalmoscopy (SLO) and swept source Fourier domain optical coherence tomography (SSOCT) imaging modes in a single compact clinical prototype platform. The SSOCT channel operates at a wavelength of 1 5m for increased penetration and visualization of the choriocapillaris and choroid, sites of major disease activity for DR and wet AMD. The system is designed to operate on a broad clinical population with a dual deformable mirror (DM) configuration that allows simultaneous low- and high- order aberration correction. The system also includes a wide field line scanning ophthalmoscope (LSO) for initial screening, target identification, and global orientation;an integrated retinal tracker (RT) to stabilize the SLO, OCT, and LSO imaging fields in the presence of rotational eye motion;and a high-resolution LCD-based fixation target for presentation to the subject of stimuli and other visual cues. The system was tested in a limited number of human subjects without retinal disease for performance optimization and validation. The system was able to resolve and quantify cone photoreceptors across the macula to within ~0.5 deg (~100-150 5m) of the fovea, image and delineate ten retinal layers, and penetrate to resolve targets deep into the choroid. In addition to instrument hardware development, analysis algorithms were developed for efficient information extraction from clinical imaging sessions, with functionality including automated image registration, photoreceptor counting, strip and montage stitching, and segmentation. In collaboration with ophthalmologists and researchers at University of Pittsburgh Medical Center (UPMC) Eye Center, we propose to continue instrument development and full clinical testing in Phase II. The multimodal AO instrument will be refined and enhanced for clinical operation, including upgrades of the retinal tracker and synchronization hardware. In addition, we will outfit the instrument with a piezo-driven reference mirror for measurement of power Doppler signals from fine retinal capillaries. The system will be installed at UPMC for a two-stage clinical trial including initial validation in subjects without retinal disease and tests in subjects with glaucoma, DR, AMD, and RP. The study will demonstrate that the multimodal AO system provides structural and flow information not currently available from any other commercially- available imager. If successful, the Phase II program and subsequent Phase III commercial development will provide clinicians with high-resolution, high performance adaptive optics imaging to help guide therapies, develop new drugs, and improve patient outcomes. PUBLIC HEALTH RELEVANCE: By making high-resolution ocular access more widespread, the proposed high performance multimodal AO instrument will bring adaptive optics technology into use by a greater number of clinicians and scientists. These researchers will, in turn, use this tool to increase our understanding of vision and its disruption by disease and to measure tissue effects of new drugs and therapies.